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SNARE Proteins Mediate α-Synuclein Secretion via Multiple Vesicular Pathways

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Abstract

The cell-to-cell transmission of pathological α-synuclein (α-syn) has been proposed to be a critical event in the development of synucleinopathies. Recent studies have begun to reveal the underlying molecular mechanism of α-syn propagation. As one of the central steps, α-syn secretion is reported to be Ca2+-dependent and mediated by unconventional exocytosis. However, the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) requirement and vesicle identity of α-syn secretion remain elusive. Here we found that α-syn secretion is SNARE-dependent by systematically knocking down Q-SNAREs and R-SNAREs in exocytosis pathways. α-Syn secretion was mainly mediated by syntaxin 4 (STX4) and synaptosomal-associated protein 23 (SNAP23), but did not require STX1 and SNAP25, in differentiated SH-SY5Y cells. On the other hand, vesicle-associated membrane protein 3 (VAMP3), VAMP7, and VAMP8 were all involved in α-syn secretion, most likely in overlapping pathways. Application of super-resolution microscopy revealed localization of both endogenous and overexpressed α-syn in endosomes, lysosomes, and autophagosomes in rat primary cortical neurons. α-Syn co-localized with microtubule-associated protein 1 light chain 3 (LC3) most extensively, suggesting its tight association with the autophagy pathway. Consistently, α-syn secretion was regulated by the autophagy-lysosome pathway. Collectively, our data suggest that α-syn secretion is SNARE-dependent and is mediated by multiple vesicular pathways including exocytosis of recycling endosomes, multivesicular bodies, autophagosomes, and lysosomes.

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Data Availability

All data generated or analyzed during this study are included in this manuscript.

Code Availability

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Abbreviations

α-syn:

Alpha-synuclein

BafA1:

Bafilomycin A1

BAPTA-AM:

1,2-Bis(o-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid acetoxymethyl ester

BFA:

Brefeldin A

CQ:

Chloroquine

DMSO:

Dimethyl sulfoxide

EDTA:

Ethylene diamine tetraacetic acid

ELISA:

Enzyme-linked immunosorbent assay

Hrs:

Hepatocyte growth factor-regulated tyrosine kinase substrate

KD:

Knockdown

LC3:

Microtubule-associated protein 1 light chain 3

LDH:

Lactate dehydrogenase

3-MA:

3-Methyladenine

MVBs:

Multivesicular bodies

PD:

Parkinson’s disease

PM:

Plasma membrane

Rab:

Member RAS oncogene family

SNARE:

Soluble N-ethylmaleimide-sensitive factor attachment protein receptor

SNAP:

Synaptosomal-associated protein

STX:

Syntaxin

TG:

Thapsigargin

VAMP:

Vesicle-associated membrane protein

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Acknowledgements

We thank Profs. Xiaomin Wang and Zhi-Qing David Xu for their valuable comments on this project and Pei Gao for drafting the schematic diagram.

Funding

This work was supported by Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (KZ201510025023); the National Natural Science Foundation of China (31471085, 91849103, 81671248); and Chaoyang District Science and Technology Plan Project (CYSF-1933).

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Authors and Affiliations

  1. Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, 100069, China

    Xiaofang Zhao, Yuan Guan, Fengwei Liu, Shuxin Yan, Yalong Wang, Yuhong Li, Rena Li & Claire Xi Zhang

  2. Department of Neurosurgery, Aviation General Hospital, Beijing, 100012, China

    Xiaofang Zhao

  3. Department of Anesthesiology, Beijing Huaxin Hospital, First Hospital of Tsinghua University, Beijing, 100069, China

    Yuan Guan

  4. Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, 48105, USA

    Meiqin Hu

  5. Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital and Beijing Institute of Brain Disorders, Capital Medical University, Beijing, 100069, China

    Rena Li

  6. Academy of Pharmacy, Xi’an Jiaotong–Liverpool University, Suzhou, 215123, China

    Claire Xi Zhang

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  1. Xiaofang Zhao
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  2. Yuan Guan
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  3. Fengwei Liu
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  7. Yuhong Li
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  8. Rena Li
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  9. Claire Xi Zhang
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Contributions

C. X. Zhang and R. Li designed research; X. Zhao, Y. Guan, F. Liu, S. Yan, Y. Wang, M. Hu, and Y. Li performed experiments; X. Zhao and Y. Guan analyzed data; and C. X. Zhang, X. Zhao, and R. Li wrote the paper. All authors read and approved the final manuscript.

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Correspondence to Rena Li or Claire Xi Zhang.

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Xiaofang Zhao, Yuan Guan, and Fengwei Liu contributed equally to the work.

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Zhao, X., Guan, Y., Liu, F. et al. SNARE Proteins Mediate α-Synuclein Secretion via Multiple Vesicular Pathways. Mol Neurobiol 59, 405–419 (2022). https://doi.org/10.1007/s12035-021-02599-0

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